1. Field of the Invention
In one of its aspects, the present invention relates to a pharmaceutical composition for regulation of organic nitrate tolerance. In another of its aspects, the present invention relates to a method for regulating organic nitrate tolerance.
2. Description of the Prior Art
Organic nitrates such as glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate, and the like are recognized as important pharmacologic agents used in the treatment of coronary artery disease and congestive heart failurexe2x80x94see Parker J. Nitrate Therapy for Stable Angina Pectoris. N Engl J Med. 1998;338:520-531. Despite successful application, the use of nitroglycerin is limited by a number of its pharmacologic characteristics. One of the important limitations is loss of efficacy during continuous therapy, a phenomenon known as xe2x80x9ctolerancexe2x80x9d. The etiology of tolerance is not clearly understood, however recent experimental data have improved the understanding of the mechanism(s) involvedxe2x80x94see one or more of:
a. Mxc3xcnzel T, Sayegh H, Freeman B A et al. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995; 95 (1):187-94;
b. Mxc3xcnzel T, Li H, Mollnau H, Hink U et al. Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability. Circ Res 2000; 86 (1): E7-E12; and
c. Mxc3xcnzel T, Mollnau H, Hartmann M et al. Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production. J Am Coll Cardiol 2000; 36 (2): 628-34.
Thus it would desirable to have a pharmaceutical composition which obviates or mitigates tolerance to organic nitrate therapy.
It is an object of the present invention to provide a novel composition which is useful to obviate or mitigate tolerance to organic nitrate therapy.
It is another object of the present invention to provide a novel method for regulating tolerance to organic nitrate therapy.
Accordingly, in one of its aspects, the present invention provides an organic nitrate therapy tolerance regulation pharmaceutical composition comprising a folate compound, a folate derivative compound, tetrahydrobiopterin and mixtures thereof, together with a pharmaceutically acceptable carrier therefor.
In another of its aspects, the present invention provides a method for regulating tolerance during organic therapy, the method comprising the step of administering to a patient undergoing organic nitrate therapy a pharmaceutical composition comprising a folate compound, a folate derivative compound, tetrahydrobiopterin and mixtures thereof, together with a pharmaceutically acceptable carrier therefor.
In yet another of its aspects, the present invention provides a pharmaceutical composition comprising:
(i) a first active ingredient comprising an organic nitrate;
(ii) a second active ingredient comprising a folate compound, a folate derivative compound, tetrahydrobiopterin and mixtures thereof; and
(iii) a pharmaceutically acceptable carrier therefor.
In yet another of its aspects, the present invention provides a kit for use in organic nitrate therapy, the kit comprising:
(i) a first pharmaceutical composition comprising an organic nitrate, together a pharmaceutically acceptable carrier therefor;
(ii) a second pharmaceutical composition comprising a folate compound, a folate derivative compound, tetrahydrobiopterin and mixtures thereof, together with a pharmaceutically acceptable carrier therefor.
In yet another of its aspects, the present invention provides a method for regulating tolerance during organic nitrate therapy, the method comprising the step of administering to a patient:
(i) a first pharmaceutical composition comprising an organic nitrate, together a pharmaceutically acceptable carrier therefor; and
(ii) a second pharmaceutical composition comprising a folate compound, a folate derivative compound, tetrahydrobiopterin and mixtures thereof, together with a pharmaceutically acceptable carrier therefor.
In yet another of its aspects, the present invention provides for the use of a compound selected from the group comprising a folate compound, a folate derivative compound, tetrahydrobiopterin and mixtures thereof for the production of a pharmaceutical composition useful in regulated tolerance to organic nitrate therapy.